Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/02—Devices for withdrawing samples
  • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/14—Process control and prevention of errors
  • B01L2200/141—Preventing contamination, tampering
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0848—Specific forms of parts of containers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/12—Specific details about materials
  • B01L2300/123—Flexible; Elastomeric
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0633—Valves, specific forms thereof with moving parts
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0633—Valves, specific forms thereof with moving parts
  • B01L2400/0638—Valves, specific forms thereof with moving parts membrane valves, flap valves
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0633—Valves, specific forms thereof with moving parts
  • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves

Definitions

• the present disclosure is directed to a sampling system and methods of obtaining samples from containers, such as bioreactors.
• a sampling system including a cassette assembly and a station base that can receive the cassette assembly, and methods of using the sampling system.
• sampling system includes a station base with a cassette-receiving surface and a plurality of actuators, and a cassette assembly received on the cassette-receiving surface.
• the cassette assembly can include a cassette base with a sample inlet, a reservoir for receiving a sample from the sample inlet, a sample outlet, and a fluid flow path extending between the sample inlet, the reservoir, and the sample outlet.
• the cassette assembly can also include a cassette top that has a plurality of movable members in engagement with respective ones of the plurality of actuators.
• the cassette assembly can also include an elastomer membrane disposed between the cassette base and the cassette top.
• One of the movable members can be in contact with the elastomer membrane to provide a sample inlet valve that can be opened and closed by a movement of one of the actuators, and the another one of the movable members can be in contact with the elastomer membrane to provide a sample outlet valve that can be opened and closed by a movement of another actuator.
• the elastomer membrane can extend over the reservoir and provides a pump membrane that is movable to vary a volume of the reservoir.
• the station base can include a pump member and the cassette top includes an air inlet disposed over a location of the reservoir that is in engagement with the pump member to vary a pressure at the pump membrane.
• the cassette base further comprises a sanitizing fluid inlet and a gas inlet and movable members that are in engagement with these inlets and additional actuators.
• the plurality of moveable members can comprise rocker valves that include a rocker arm in engagement with a respective one of the plurality of actuators and a ball that is in contact with the elastomer membrane.
• the rocker arms can be movable from a first position in which the respective valve is closed and a second position in which the respective valve is open, and each of the rocker arms can have a first end in engagement with a respective one of the plurality of actuators and a second end that is in contact with a spring member that biases the rocker arm to the first position.
• a cassette assembly in other embodiments, includes a cassette base comprising a sample inlet, a reservoir for receiving a sample from the sample inlet, a sample outlet, and a fluid flow path extending between the sample inlet, the reservoir, and the sample outlet; a cassette top comprising a plurality of movable members including at least a first movable member and a second movable member; and an elastomer membrane disposed between the cassette base and the cassette top.
• the first movable member can be in contact with the elastomer membrane to provide a sample inlet valve that can be opened and closed by a movement of the first movable member
• the second movable member can be in contact with the elastomer membrane to provide a sample outlet valve that can be opened and closed by a movement of the second movable member.
• a plurality of openings in the cassette assembly can extend from respective ones of the plurality of movable members through the elastomer membrane and the cassette base to receive a plurality of actuators therethrough.
• the elastomer membrane comprises silicone, EPDM, Viton, or CFLEX.
• a method of collecting a fluid sample from an enclosed container can include securing a cassette assembly to a station base, positioning a plurality of actuators of the station base in engagement with respective ones of the plurality of movable members, actuating one of the plurality of actuators to engage with the third movable member to open the sample inlet valve and direct the fluid sample to the reservoir, applying a pressure to the elastomer membrane above the reservoir to cause the elastomer membrane to move into the reservoir and direct the fluid sample from the reservoir to the sample outlet, actuating another one of the plurality of actuators to engage with the fourth movable member to open the sample outlet valve and direct the fluid sample out of the sample outlet, removing the first cassette assembly from the station base, and securing another cassette assembly to the station base to replace the first one.
• the plurality of actuators comprise pneumatic air cylinders, and the pneumatic air cylinders are coupled to the station base, which is connected to a gas source and a sanitizing fluid source.
• the plurality of actuators can be electric actuators.
• the cassette assembly can contain all of the wetting components of the fluid sample collection and the station base is not directly exposed to the fluid sample. In other embodiments, portions of the station base can be exposed to the fluid sample, such as at a line out.
• FIG. 1 illustrates an exemplary sampling system for obtaining a sample from a bioreactor or other similar containers or systems that support biologically and/or chemically active environments.
• FIGS. 2A-2D are schematic representations of an exemplary operation of the sampling system of FIG. 1.
• FIG. 3 illustrates an exemplary cassette assembly for a sampling system.
• FIG. 4 shows a side view of a cassette assembly coupled to a station base.
• FIG. 5 shows an exploded view of the cassette assembly and station base.
• FIG. 6 shows the exploded view of FIG. 5 from a lower perspective.
• FIG. 7 shows a cross-sectional view of the sampling system to illustrate the operation of the actuators and cassette rockers.
• FIG. 8 shows another cross-sectional view of the sampling system to illustrate the operation of the actuators and cassette rockers.
• FIG. 9 shows a top perspective view of an exemplary cassette base.
• FIG. 10 shows a bottom perspective view of an exemplary cassette base.
• FIG. 11 shows a top view of an exemplary cassette base.
• FIG. 12 shows an exemplary elastomer membrane for use with a cassette assembly.
• FIG. 13 shows a top view of a lower portion of a cassette top.
• FIG. 14 shows a bottom view of the lower portion of the cassette top of FIG. 13.
• FIG. 15 shows a bottom view of an upper portion of the cassette top.
• FIG. 16 shows a bottom perspective view of the upper portion of the cassette top with a plurality of cassette rockers and balls positioned therein.
• FIG. 17 shows a bottom view of the upper portion of the cassette assembly shown in FIG. 16.
• FIG. 18 shows a perspective view of an exemplary station base.
• FIG. 19 shows a perspective view of a cassette assembly secured to the station base of FIG.
• FIG. 20 shows a cassette assembly with another exemplary station base.
• the singular forms“a,”“an,” and“the” include the plural forms unless the context clearly dictates otherwise.
• the term“includes” means“comprises.”
• the term“coupled” or“secured” encompasses mechanical and chemical couplings, as well as other practical ways of coupling or linking items together, and does not exclude the presence of intermediate elements between the coupled items unless otherwise indicated, such as by referring to elements, or surfaces thereof, being“directly” coupled or secured.
• the term“and/or” means any one item or combination of items in the phrase.
• the term“exemplary” means serving as a non-limiting example, instance, or illustration.
• the terms“e.g.,” and“for example,” introduce a list of one or more non-limiting embodiments, examples, instances, and/or illustrations.
• upstream and downstream are not absolute terms; instead, those terms refer to the direction of flow of fluids within a channel or pathway.
• a first area is “upstream” of a second area if the fluid flows from the first area to the second area.
• the second area can be considered “downstream” of the first area.
• FIG. 1 illustrates a sampling system 100 for obtaining a sample from a bioreactor 102 or other similar containers or systems that support biologically and/or chemically active environments.
• Sampling system 100 includes a sample collection valve 104 that can open to allow a sample to enter a fluid flow path 106. The sample can be delivered along the flow path 106 to an outlet valve 108. Outlet valve 108 can open or close to allow or restrict, respectively, the flow of samples through outlet valve 108. After the sample exits outlet valve 108, the sample can be directed into an isolated chamber or container 110 for analysis, processing, and/or delivery to another system for analysis and/or processing. For example, the sample can be directed from chamber 110 to an automated analyzer 112, such as a bioprofile analyzer available from Nova Biomedical of
• the samples that are dispensed from outlet 108 for analysis or processing are desirably representative of the materials in bioreactor 102 at the time the sample was taken.
• a sanitizing fluid can be delivered through a portion of flow path 106 that comes into contact with the samples.
• a sanitizing fluid inlet valve such as valve 114 or 116, is provided upstream of sample collection valve 104.
• the sanitizing fluid inlet valve 114, 116 is operable between a closed position that restricts fluid flow through sanitizing fluid inlet valve and an open position that allows fluid flow through sanitizing fluid inlet valve. In some embodiments, some or all of the valves can be biased closed.
• a“sanitizing fluid” is any fluid that can sanitize, disinfect, or sterilize the valve.
• the sanitizing fluid can be a liquid, a gas, or a combination thereof.
• Sanitizing fluids include steam, ethylene oxide, glutaraldehyde, formaldehyde, formalin, chlorine gas, hypochlorite, bromine, hypobromite, iodine, hypoiodite, bromine chloride, chlorine dioxide, ozone, hydrogen peroxide, monochloramine, dichloramine, trichloramine, quatinary ammonium salts, ethanol, 70% ethanol/water, isopropanol, 70% isopropanol/water, peroxyacetic acid, and peracetic acid.
• the sanitizing fluid is steam.
• the sanitizing fluid is ethylene oxide.
• the sanitizing fluid is glutaraldehyde.
• a gas inlet valve such as valve 114 or 116 (whichever is not used as the sanitizing fluid inlet valve) can also be provided upstream of sample collection valve 104 to deliver a gas through flow path 106.
• the gas can eliminate and/or reduce the amount of sanitizing fluid remaining within flow path 106 after flow path 106 is exposed to the sanitizing fluid.
• the sanitizing fluid can clean the path and/or remove any material from previous samples in the area contacted by the sanitizing fluid.
• the gas inlet valve is operable between a closed position that restricts the flow of gas through the gas inlet valve and an open position that allows the flow of gas through the gas inlet valve.
• the gas comprises compressed air.
• variable volume reservoir 118 can be provided downstream of sample collection valve 104.
• Variable volume reservoir 118 can be moveable between a first position and a second position to draw a sample through sample collection valve 104 and into flow path 106.
• the sample can be drawn into at least a portion of variable volume reservoir 118 along a first portion of flow path 106 and discharged from variable volume reservoir 118 along a second portion of flow path 106.
• Variable volume reservoir 118 can comprise a diaphragm pump as shown in FIG. 1, which can draw in a sample using a vacuum generated on the pump side.
• sampling system 100 can comprise a unitary structure 120.
• unitary structure 120 can comprise sample collection valve 104, sanitizing fluid inlet valve and gas inlet valve 114, 116, outlet valve 108, and at least a portion of the fluid flow path.
• the entire flow path between the sanitizing fluid inlet valve 114 and the outlet valve 108 is internal to the unitary structure 120.
• one or more filters 122 can be provided upstream of gas inlet valve, sanitizing fluid inlet valve 114, 116 to ensure that the gas or sanitizing fluid that enters flow path 106 is substantially free of impurities and/or contaminants.
• filters 122 e.g., a sterile air filter
• FIGS. 2A-2D are schematic representations of the operation of sampling system 100.
• sampling system 100 can be coupled to bioreactor 102 and can operate to sanitize or sterilize a flow path from the sanitizing fluid inlet valve 114, 116 through through the closed pathway of flow path 106, including sample collection valve 104, reservoir 118 (e.g., a diaphragm pump), and outlet valve 108.
• sample collection valve 104 e.g., a diaphragm pump
• outlet valve 108 e.g., a diaphragm pump
• FIG. 2A illustrates a sanitizing procedure in which a sanitizing fluid 124 (e.g., steam) is directed into flow path 106 through an open sanitizing fluid inlet valve 114 (in this embodiment).
• a sanitizing fluid 124 e.g., steam
• sanitizing fluid 124 is directed along flow path 106, including along the portions of flow path 106 that are in contact with a sample drawn from bioreactor 102 and dispensed along the flow path 106.
• sanitizing fluid 124 is directed along flow path 106 past sample collection valve 104, through variable volume reservoir 118, and out outlet valve 108.
• sanitizing fluid 124 comes into contact with the internal surfaces that define flow path 106, those surfaces are sanitized or sterilized.
• sanitizing fluid inlet valve 114 (in this embodiment) is closed and gas inlet valve 116 (in this embodiment) is opened to allow a gas 126 (e.g., air) to enter flow path 106.
• gas 126 can also be directed along flow path 106, including along the portions of flow path 106 that sanitizing fluid 124 contacts. In this manner, any remaining sanitizing fluid 124 can be purged from flow path 106.
• FIG. 2C illustrates the operation of variable volume reservoir 118 to draw a sample 128 from bioreactor 102 through open sample collection valve 104.
• variable volume reservoir 118 comprises a diaphragm pump that moves from a first volume to a second, larger volume as illustrated by arrow 132. The enlargement of the volume of variable volume reservoir 118 draws a sample through open sample collection valve 104 and into flow path 106.
• Variable volume reservoir 118 has an inlet 134 and an outlet 136. After sample 128 is drawn into variable volume reservoir 118, the diaphragm pump moves from the second, larger volume back to a smaller volume as illustrated by arrow 132 in FIG. 2D.
• variable volume reservoir 118 discharges sample 128 through outlet 136 of variable volume reservoir 118.
• Sample 128 is then discharged through outlet valve 108 to be captured for analysis and/or further processing.
• a valve 138 can be provided downstream of outlet valve 108.
• Valve 138 can be closed to cause sample 128 to be directed into chamber 110.
• Valve 138 can be configured to open to allow the discharge of waste.
• the discharged waste can include, for example, sanitizing fluid and purging gas that has traveled along the flow path 106 to sanitize and purge excess sample materials from flow path 106.
• the sampling systems described herein can include systems that have a reusable component that does not require sterilization between operations and a single-use component that is replaced between operations.
• the station base can contain all the required mechanical actuators (such as the pneumatic air cylinders or electric actuators, and variable volume pump components) and can be connected (e.g., plumbed) to the control system and purge air and sanitant sources.
• FIG. 3 illustrates the replaceable component (e.g., the unitary structure 120) of the sampling system as a cassette assembly.
• the cassette assembly can include all of the wetting components of the sampling system that come into direct contact with fluid.
• the term“wetting component” as used herein means a component that comes in direct contact with a fluid (gas and/or liquid) and are typically include, for example, reservoirs, conduits, filters, and combinations thereof.
• the term“cassette” as used herein means a cartridge or other structure capable of fitting and/or connecting to a sample inlet and one or more other fluid connections.
• the cassette can be a replaceable and/or disposable self-contained unit (e.g., a unitary structure) containing all wetting components of a sampling system of the type described herein.
• the terms “disposable” refer to an element, component, and/or structure that may be disposed with and/or replaced after no more than 10 uses, preferably no more than 5 uses, preferably no more than 2 uses, most preferably no more than 1 use.
• the term“single use” refers to a system that is used once.
• the term“uses or use,” as used herein, means a sampling procedure that includes receiving a first type or kind of sample before changing to receive a different kind or type of sample.
• FIG. 3 illustrates a cassette assembly 200 that includes a cassette base 202, a cassette top 204, and an elastomer membrane 206 disposed (e.g., fitted or assembles) between the cassette base 202 and cassette top 204.
• a plurality of valve ports are provided in the cassette base and each can be coupled to a tube or other conduit for coupling with other components of the sampling system.
• FIG. 3 illustrates a first tube 208, which can be coupled to a gas source for delivering a gas to purge sanitizing fluid from the flow path 106, and a second tube 210, which can be coupled to a sanitizing fluid source to deliver sanitizing fluid to the flow path 106.
• a third tube 212 can be coupled to the bioreactor at sample outlet 205 to receive a sample.
• the elastomer membrane can be formed of any suitable elastomeric materials (such as, for example, silicone, ethylene propylene diene monomers (EPDM), Viton, and CFLEX) that can serve as a sealing surface for the plurality of valve ports and also as a pump membrane for the variable volume reservoir as described in detail below.
• the cassette assembly 200 can be coupled to a station base 214.
• Station base 214 can engage with the cassette assembly 200 so that a plurality of pneumatic air cylinders (or other actuators, such as electric actuators) can engage with a plurality of cassette rockers (or rocker arms) to open and close a plurality of valve ports in the cassette assembly 200.
• cassette rocker or“rocker arm” refers to a structure that can pivot and/or move between at least two positions when a force is applied at one or both ends.
• the pneumatic air cylinders are actuators that are in engagement with the cassette rockers, which are movable members that can move from a first position to a second position causing the elastomer membrane to move and open and close the valve defined by an opening and the elastomer membrane (e.g., a sample inlet valve, sample outlet valve, sanitizing fluid inlet valve, and/or gas inlet valve).
• the term“in engagement” refers to an actuator or actuating member that is positioned so that it can engage with another structure to cause it to move. Therefore, a component can be“engaged” with an actuator even if the two are not in direct contact, so long as the actuator is in position so that it can cause the movement of the other component.
• first extension member 240 extends through an opening 242 in lower portion 234, an opening 244 in elastomer membrane 206, and an opening 246 in cassette base 202.
• first extension member 240 can also extend though a cassette tube retaining member 248 (shown in FIG.
• each cassette rocker can be biased to a closed position by a spring member 250, which can be retained by a respective spring retaining well 252 (as shown in FIG. 6.).
• FIGS. 7 and 8 illustrate the operation of the pneumatic air cylinders and cassette rockers.
• each cassette rocker engages with a ball 254 to provide a rocker valve that can engage with the elastomer membrane 206 to open and close a respective valve port.
• FIG. 7 illustrates a rocker valve 258 in a closed state
• FIG 7 illustrates the same valve in an open state.
• an actuator nose 256 of pneumatic air cylinder 216 does not engage with the cassette rocker 226 of rocker valve 258. Instead, spring member 250 biases the cassette rocker 226 into engagement with ball 254, with ball 254 forcing a portion of the elastomer membrane 206 into engagement with the valve port 260.
• the pneumatic air cylinder 216 has been actuated and the actuator nose 256 extends into contact with an end 262 of cassette rocker 226.
• the tilting of the cassette rocker 226 causes the spring member 250 to compress and reduces the force of the cassette rocker 226 on the ball 254.
• the force of the ball 254 on the elastomer membrane 206 likewise reduces, causing the valve port 260 to open and permit bi directional flow therethrough.
• FIGS. 9-11 show additional details of a cassette base 302.
• the cassette base includes a plurality of valve ports that can be coupled to a tube or other conduit for coupling with other components of the sampling system, and opened and closed by a respective rocker valve.
• the plurality of valve ports can include a sample collection port 304, a sanitizing fluid inlet port 314, a gas inlet port 316, and a cavity 315 that, in part, defines reservoir 318.
• the reservoir 318 is also defined by the respective cavity of the lower portion 334 of the cassette top, as shown in FIG. 14.
• the volume of the reservoir 318 can vary depending on the position of the elastomer membrane as shown in FIGS. 2A-2D.
• a sample can enter the fluid flow path 306 and be delivered to the reservoir 318 as shown in FIG. 2C.
• the elastomer membrane is caused to move into the reservoir where the sample is located and force the sample out of the reservoir as shown in FIG. 2D.
• the sample exit the outlet port 305, which has been moved into the open state or position.
• FIG. 10 shows a bottom view of cassette base 302, which shows respective openings in fluid connection with the valve ports of the cassette base. These openings can receive and couple to respective tubes or conduits.
• coupling members 360, 362, 364, and 366 can receive tubes or conduits in fluid connection with sample collection port 304, a sanitizing fluid inlet port 314, a gas inlet port 316, and outlet port 305, respectively.
• FIG. 11 illustrates a top view of the cassette base 302.
• This view clearly shows a plurality of openings 370 in the cassette base 302 for the actuators (e.g., pneumatic air cylinders), which pass through the cassette base to engage with the cassette rockers in the cassette top 204.
• a plurality of alignment openings 372 are shown. These alignment openings 372 receive the extending portions 238 (fingers) of the upper portion 236 of the cassette top 204.
• FIG. 11 also shows an air flow opening 374. Opening 374 is in fluid connection with an area above the elastomer membrane to allow the reservoir to change its volume (i.e., to operate as a diaphragm pump). Air flow opening permits in the cassette base allows for the pump to be connected to a lower surface of the cassette base, which can be advantageous.
• FIG. 12 shows the elastomer membrane 206.
• the elastomer membrane has a plurality of openings 370 for the pneumatic air cylinders, a plurality of alignment openings 372, and an air flow opening 374.
• FIGS. 13 and 14 illustrate the lower portion 234 of the cassette top 204.
• FIG. 13 shows a top view
• FIG. 14 shows a bottom view.
• the lower portion 234 of the cassette top 204 has a plurality of openings 370 for the pneumatic air cylinders, a plurality of alignment openings 372, and an air flow opening 374.
• a channel 376 is provided in the top surface of the lower portion 234. This channel extends from air flow opening 374 to another opening 378 which is in fluid connection with a portion of the reservoir above the elastomer membrane.
• the channel 376 and openings 374, 378 cooperate to allow air from the pump to be delivered through the cassette assembly to a location in the reservoir and above the elastomer membrane.
• FIGS. 13 and 14 also show the respective ball-receiving openings 380, which are sized to receive the balls 254, so that they can move downward to engage with the elastomer membrane and close a respective valve port, and upward to disengage with the elastomer membrane and open a respective valve port.
• FIG. 13 also shows the rocker guides (e.g., channels) which receive the cassette rockers.
• FIGS. 15-17 show the upper portion 236 of cassette top 204, with the rocker valves (FIGS. 16 and 17) and without (FIG. 15).
• upper portion 236 encloses the rocker guides and has a plurality of extending portions 238 (e.g., fingers) that engage with openings that extend through the cassette assembly to align and secure the respective components of the cassette assembly 200 in a desired orientation.
• FIG. 15 also indicates a recess 278 that receives an O-ring 280 (FIGS. 16 and 17) that provides a sealing surface for the channel 376 in lower portion 234.
• each cassette rocker 226, 228, 230, 232 are retained within a respective rocker guides in a lower portion 234 (not shown in these figures for convenience) and biased away from the upper portion 236 of the cassette top 204 by a spring member 250.
• Each cassette rocker can have a receiving surface 282 that engages with a respective actuator nose of a pneumatic air cylinder.
• FIG. 18 illustrates one exemplary station base 214 on which a cassette assembly can be received.
• FIG. 19 illustrates the same station base 214 with a cassette assembly received on a surface of the station base 214 and secured thereto with a plurality of gripping members 284, such as spring-loaded clamps.
• FIG. 20 illustrates another exemplary station base and attachment means.
• a cassette assembly 200 can be received on a surface of station base 214.
• Station base 214 comprises the plurality of pneumatic air cylinders 216, 218, 220, 222, which engage with the cassette rockers as described above.
• the tubes 208, 210, 212 of the cassette assembly 200 can be coupled additional tubing (e.g., using quick-connect fittings) to deliver and/or receive fluids from and to other areas of the system as discussed herein.
• the sample can flow out outlet valve 108 (FIG. 1) and transition to the station base 214 via a seal (e.g., an o-ring seal) between the cassette assembly 200 and station base 214 at coupling 366 (FIG. 10).
• a seal e.g., an o-ring seal
• the coupling of the cassette assembly 200 and base station 214 is achieved by a clamp member 290, which has a handle 292 (e.g., a lever) and a cassette-engaging member 294 (e.g., a clamping plate or surface).
• a handle 292 e.g., a lever
• a cassette-engaging member 294 e.g., a clamping plate or surface.
• the loading and unloading of a cassette assembly can comprise a spring-loaded system that ejects an old cassette assembly and, upon receipt of a new cassette assembly, automatically closes to load the new cassette assembly on the station base.
• the cassette assemblies described herein can be disposable (or“single-use” components) to allow for quick transitions from a first sampling procedure to a second sampling procedure (either with the same or a different type of sample), while the station base and related components (e.g., pneumatic air cylinders, clamping members) can be used without requiring sterilization.
• the station base and related components e.g., pneumatic air cylinders, clamping members
• the single-use cassette assembly can be readily sterilized, such as by gamma and/or autoclave sterilization.
• the cassette assembly can be gamma compatible and pre-attached to other sterile sampling system components, such as bioreactor bags or pre-formed bioreactor vessels, prior to gamma sterilization, thereby eliminating the need to make an aseptic connection during setup.
• the entire structure 120 can be sterilized by, for example, gamma radiation, autoclave, or another approach, and connected to bioreactor 102 in a sterile fashion (such as sterile tube welding or a sterile single use connector).
• a sterile fashion such as sterile tube welding or a sterile single use connector.
• the structure 120 would need to be connected to bioreactor 102 and the entire assembly sterilized (gamma radiation, autoclave, etc.).
• the cassette assemblies described herein also reduce the number of moving parts and connections that can be potential sources of sample contamination. Instead, the valve ports engage with a single diaphragm member (e.g., the elastomer membrane), thereby reducing sliding interfaces and other sources of potential contamination.
• a single diaphragm member e.g., the elastomer membrane
• the sampling systems described herein can be easily scaled up and down in size as desired.
• the pump volume of the sampling system is less than 20 mL, less than 10 mL, less than 5 mL, less than 3 mL, and, in other embodiments, less than 2 mL, such as about 1 mL.
• the sampling system can draw samples in relatively small increments from a dip tube or other sterile connector.

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• 2020
  • 2020-04-27 EP EP20723548.2A patent/EP3965931A1/de active Pending
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  • 2020-04-27 US US17/609,144 patent/US12498299B2/en active Active
• 2025
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